PT  - JOURNAL ARTICLE
AU  - Barbara Gonzalez-Teran
AU  - Maureen Pittman
AU  - Franco Felix
AU  - Desmond Richmond-Buccola
AU  - Reuben Thomas
AU  - Krishna Choudhary
AU  - Elisabetta Moroni
AU  - Giorgio Colombo
AU  - Michael Alexanian
AU  - Bonnie Cole
AU  - Kaitlen Samse-Knapp
AU  - Michael McGregor
AU  - Casey A. Gifford
AU  - Ruth Huttenhain
AU  - Bruce D. Gelb
AU  - Bruce R. Conklin
AU  - Brian L. Black
AU  - Benoit G. Bruneau
AU  - Nevan J. Krogan
AU  - Katherine S. Pollard
AU  - Deepak Srivastava
TI  - Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes
AID  - 10.1101/2021.01.05.423837
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.05.423837
4099  - http://biorxiv.org/content/early/2021/01/05/2021.01.05.423837.short
4100  - http://biorxiv.org/content/early/2021/01/05/2021.01.05.423837.full
AB  - Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants among proteins that interact with GATA4 or TBX5. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes, resulting in co-activation, and the GLYR1 missense variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.Competing Interest StatementD.S. is scientific co-founder, shareholder and director of Tenaya Therapeutics. B.G.B. and B.R.C. are scientific co-founders and shareholders of Tenaya Therapeutics. K.S.P. and N.K. are shareholders of Tenaya Therapeutics.